This project integrates basic and clinical research in a bench to bedside approach to the challenges of human disease. Most disorders affecting the nervous system are characterized by a wide range of patient presentations, yet the factors contributing to this heterogeneity are often elusive. Gaucher disease, the most common of the sphingolipidoses, is studied as a prototype for many disorders affecting the nervous system because there is a broad spectrum of clinical diversity resulting from this recessively inherited enzyme deficiency. Gaucher disease affects approximately 10,000 to 20,000 Americans and is more common among Ashkenazi Jews. Clinical, molecular, and biochemical studies in humans and animals are used to enhance our understanding of heterogeneity in Gaucher disease and our ability to develop rational therapy for patients. The techniques, insights, and experience gained are then applied to other less characterized disorders and ultimately to the challenges of complex psychiatric illnesses. Our clinical and molecular studies have shown that there is significant genotypic heterogeneity among clinically similar patients, and that the vastly different phenotypes encountered among patients with Gaucher disease, as well as with many other disorders, are not adequately predicted by genotype. Recombination events within and around the glucocerebrosidase locus, and newly discovered contiguous genes, may potentially have a critical role. Transgenic and knock-out mice (see Project #Z01-MH 02656-06) are used to facilitate our understanding of the pathogenesis and treatment of lysosomal storage disorders and the phenotypic consequences of specific genotypes. The null allele type 2 Gaucher mouse led to the recognition of a new human Gaucher phenotype, the appreciation of the role of glucocerebrosidase in skin morphology and function, and a means to presymptomatically distinguish the acute neurologic from the non-neurologic Gaucher phenotypes. A second murine model enabled the identification of a novel contiguous gene, metaxin. Understanding mechanisms leading to diverse phenotypes will provide insights relevant to other disorders. - Gaucher disease, nervous system, enzyme deficiency, genotype, recombination, knock-out mice, glucocerebrosidase, skin morphology, murine model - Human Subjects